# Stress Pathways in the Induction of Metaplasia

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2020 · $26,867

## Abstract

PROJECT SUMMARY
Stress Pathways in the Induction of Metaplasia
Mature cells in many organ systems can undergo a reprogramming event in which cells dedifferentiate, convert
to a progenitor-like state, and enter the cell cycle in response to tissue injury. This cell state change results in
the formation of metaplasia to repair lost and damaged tissue. If tissue is unable to return to normal after
metaplasia formation this is a risk factor for cancer formation, as is the case with spasmolytic polypeptide-
expressing metaplasia in the stomach and acinar-to-ductal metaplasia in the pancreas. The cellular and
molecular mechanisms that govern injury-induced metaplasia formation are largely undescribed, yet they
appear to occur in a consistent, step-wise manner: 1. Autodegradation of differentiated proteins, 2. Expression
of a progenitor/metaplastic gene network, and 3. Entry to the cell cycle. A recent publication from our lab
demonstrated that these steps are conserved in mouse injury models in the stomach, pancreas, liver, and
kidneys. The experiments presented in this proposal aim to interrogate the importance of two proteins known
to be involved in the integrated stress response, eukaryotic initiation factor 2 (eIF2) and activating transcription
factor 3 (ATF3), during the development of metaplasia. Preliminary results show that eIF2 becomes inactivated
rapidly after injury in mouse models that induce pancreatic and gastric metaplasia. ATF3 protein and Atf3
mRNA also rapidly increase in these injury models concurrent with eIF2 inactivation. The Aims presented here
will further determine if Atf3 function and eIF2 inactivation are necessary components of metaplasia initiation
with detailed mechanistic studies using Atf3-null mice, pharmacological inhibitors of eIF2, and an injury model
in Caco-2 cell lines. Experiments will also determine how eIF2 becomes inactivated in this injury response and
identify genes differentially expressed by ATF3. If the experiments presented here support the hypothesis that
eIF2 and ATF3 are critical for mature cell reprogramming following injury, future studies will determine the
importance of eIF2 and ATF3 in human gastric and pancreatic metaplasia and adenocarcinoma.

## Key facts

- **NIH application ID:** 9836609
- **Project number:** 5F31CA236506-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Megan DeAnna Radyk
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $26,867
- **Award type:** 5
- **Project period:** 2018-12-01 → 2020-09-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836609

## Citation

> US National Institutes of Health, RePORTER application 9836609, Stress Pathways in the Induction of Metaplasia (5F31CA236506-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9836609. Licensed CC0.

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